At present, there has not yet been explored a chemotherapeutic agent that exerts a satisfactory result for inflammatory diseases such as sepsis and hepatitis, and there have been only applied steroids, anti-inflammatories, platelet aggregation inhibitors, vasodilators, antibiotics, etc., as supportive measures to the above diseases. Since these inflammatory diseases exhibit serious symptoms in many cases, there has been desired an exploitation of therapeutically effective agents with no or lesser side-effects but with safeness.
It is known that many cytokines are involved in various inflammatory diseases in living bodies. Examples of such inflammatory cytokines include a number of tumor necrosis factor (TNF-α), interleukins (ILs) such as IL-1, IL-6 and IL-12, and interferon (IFN)-γ, which have pharmacological actions other than their relation to inflammations. Among which, TNF-α was once discovered as a cytokine having an anti-tumor activity and it has been expected as an anti-cancer drug; however, after which it was revealed to be the same substance as cachectin, i.e., a cachexia-inducing factor. Further, TNF-α has an action of stimulating the production of other cytokines such as IL-1, etc., as well as actions of proliferating fibroblasts, inducing endotoxin shock, and inducing arthritis such as cartilage-destructing action; and it is suggested that inflammatory diseases have a causal correlation with the abnormal production of TNF-α (see, for example, Japanese Patent Laid-Open No. 25251/98, Japanese Unexamined Patent Application Publication No. 505812/97, Japanese Patent Laid-Open No. 130149/98, and International Patent Publication No. WO03/007974).
Among inflammatory diseases in which the abnormal production of TNF-α is deemed involved, for example, a serious one of resulting in a catastrophic outcome such as cardiac asystole/death after the condition of acute cardiovascular failure such as endotoxin shock induced by sepsis accompanied by bacterial infection. Further, TNF-α has been also suggested to be involved in the fulminant of rheumatoid arthritis (RA), acute respiratory distress syndrome (abbreviated as “ARDS”, hereinafter), and autoimmune or viral hepatitis; and in the occurrence or the exacerbation of acute and serious clinical conditions such as inflammatory bowel disease.
Recently, as a therapeutic agent for inflammatory diseases to inhibit the abnormal production of TNF-α, an anti-TNF-α antibody (see, for example, Japanese Patent Laid-Open No. 25251/98 and Japanese Unexamined Patent Application Publication No. 505812/97) and TNF-α production inhibitor (see, for example, Japanese Patent Laid-Open No. 130149/98 and International Patent Publication No. WO03/007974) have been tried to apply for the treatment of such inflammatory diseases; however, no satisfactory effect has not yet been attained thereby, and in some cases, a relatively long term administration thereof may cause side effects as a problem.
Also, adenosine as an endogenous purine nucleotide relates to the regulation of various biological reactions via the binding onto cell surface receptors. There exists a finding that adenosine has an anti-inflammatory action and an ischemic injury inhibitory action, however, it has relatively strong systemic side-effects. Furthermore, adenosine is promptly absorbed by hematocytes and vascular endothelial cells in the blood, metabolized and hydrolyzed to lose its action within a relatively short period of time. Because of this, clinical application thereof is limited. To compensate for the defect and to increase the concentration of adenosine at inflammatory sites, as well as to decrease the expression of the systemic side-effects, the exploitation of inhibitors for intracellular-intake of adenosine has been also under way (see, for example, “Folia Pharmacological Japonica”, Vol. 122, pp. 121-134, 2003).